In vitro studies have shown that antitumor activity can be enhanced when cytotoxic drugs are used in combination. This has led, over the years, to the use of drug combinations in the clinic such that cytotoxic drug combinations are now standard in many forms of cancer chemotherapy. New anticancer drugs are typically first introduced in patients as single agents. After a maximum tolerated dose is determined for one agent, a second agent is added and the dose of one or both agents is adjusted on the basis of toxicity. Usually the more active or efficacious agent is used at full dose and the other agent is dose reduced and titrated upward in dose until dose limiting toxicity defines the maximum tolerated dose for the combination. As a result the development of most combination regimens is determined empirically on the basis of tolerability. However, in vitro, where the molar ratio of drugs used in combination can be controlled, it has been demonstrated that drug combinations providing synergy at one ratio may be simply additive or even antagonistic at other ratios (Mayer, L. D., et al., Mol. Cancer. Ther. (2006) 5:1854-1863). When individual free drugs are administered in chemotherapy “cocktails”, each agent is handled differently by the body, resulting in varying distribution and elimination of each drug, which can result in drug ratios that are suboptimal or ineffective for some or most of the time. The observation that in vitro synergistic activity of antineoplastic drugs depends on specific drug ratios suggests that the in vivo and clinical activity of a combination may be enhanced by maintaining the synergistic ratio. In this way, the development of particular combination chemotherapeutic regimens can be based on the most efficacious ratio rather than empirically based on toxicity.
Combination chemotherapies comprising cytidine analogues and anthracycline agents have been well studied for treatment against various cancers or hematologic proliferative disorders. Drug cocktails of the cytidine analogue, cytarabine, and an anthracycline such as daunorubicin demonstrate some efficacy in patients with hematologic malignancies. See, e.g., Tallum, et al., Blood (2005) 106:2243. Since 1973, cytarabine combined with an anthracycline has been the standard first-line therapy for acute myelogenous leukemia (AML), against which other regimens are compared. At present, the standard of care for AML is a combination of cytarabine and daunorubicin administered in the classic “7 and 3” regimen with cytarabine administered for 7 consecutive days and daunorubicin for the first 3 of those 7 consecutive days.
Cytarabine (cytosine arabinoside, Ara-C or 1-β-D-arabinofuranosylcytosine) is a cell cycle phase-specific antineoplastic agent, affecting cells predominantly during the S-phase of cell division. Intracellularly, cytarabine is converted into cytarabine-5′-triphosphate (ara-CTP), which is the active metabolite. The mechanism of action is not completely understood, but it appears that ara-CTP acts primarily through inhibition of DNA polymerase. Incorporation into DNA and RNA may also contribute to cytarabine cytotoxicity. Cytarabine is cytotoxic to a wide variety of proliferating mammalian cells in culture.
Daunorubicin hydrochloride is the hydrochloride salt of an anthracycline cytotoxic antibiotic produced by a strain of Streptomyces coeruleorubidus. Daunorubicin has antimitotic and cytotoxic activity through a number of proposed mechanisms of action. Daunorubicin forms complexes with DNA by intercalation between base pairs. It inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes. Single strand and double strand DNA breaks result. Daunorubicin may also inhibit polymerase activity, affect regulation of gene expression, and produce free radical damage to DNA. Daunorubicin possesses an antitumor effect against a wide spectrum of animal tumors, either grafted or spontaneous.
While combinations of these two drugs administered as drug cocktails have provided some benefit, there are various drawbacks that limit their therapeutic use. For instance, administration of free drug cocktails typically results in rapid clearance of one or all of the drugs before reaching the disease site. If the individual drugs in the cocktail are only optimally effective within a narrow ratio to one another, a rapid clearance of one drug but not the other can reduce overall efficacy of the combination while increasing toxicity. This can sometimes lead to increased toxicity as individual drug dosages are increased to achieve a greater therapeutic effect. Attempts to improve activity and reduce toxicity also can include longer infusion times. For example, the current administration of cytarabine which is either given in high doses (1 gram/m2/day) by slow bolus over 1 hour/day or in lower, more typical, doses (100-200 mg/m2/day) by continuous infusion for the 7 consecutive days. Such long infusional administration results in increased complexity, hospitalization time, and expense as well as increased risk of infusion complications.
Addition of other agents such as 6-thioguanine or etoposide and changes in the dose or schedule of administration have been studied to improve outcomes, but while incremental gains have been made, the 30-year old use of an anthracycline and cytarabine remains the basis for standard induction treatment in AML. Therefore, in order to substantially improve overall survival in the disease along with lowered toxicity, there is a need for more effective and better-tolerated induction and/or consolidation therapies.
Drug delivery regimens for these agents, such as those identified here, that permit the sustained delivery of non-antagonistic drug ratios are highly desirable as they will permit reduced administration times without increasing toxicity or decreasing efficacy of the treatment. Such improvements in regimens may also permit more effective doses to be administered to the patient than would be possible with other regimens that otherwise are limited by toxicity.